Toxicogenomic analysis of N-nitrosomorpholine induced changes in rat liver: Comparison of genomic and proteomic responses and anchoring to histopathological parameters

Journal Article · Tue Dec 01 00:00:00 EST 2009 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.08.020· OSTI ID:21344805

Oberemm, A ^[1]; Ahr, H -J ^[2]; Bannasch, P ^[3]; Ellinger-Ziegelbauer, H ^[2]; Glueckmann, M ^[4]; Hellmann, J ^[5]; Ittrich, C; Kopp-Schneider, A ^[3]; Kramer, P -J ^[5]; Krause, E ^[6]; Kroeger, M ^[5]; Kiss, E ^[3]; Richter-Reichhelm, H -B ^[1]; Scholz, G ^[2]; Seemann, K ^[5]; Weimer, M ^[3]; Gundert-Remy, U ^[1]

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1. Federal Institute for Risk Assessment (BfR), 14195 Berlin (Germany)
2. Bayer Schering Pharma AG, Special Toxicology, 42096 Wuppertal (Germany)
3. German Cancer Research Center (DKFZ), 69120 Heidelberg (Germany)
4. Applied Biosystems Deutschland GmbH, 64293 Darmstadt (Germany)
5. Merck KGaA, Institute for Toxicology, 64293 Darmstadt (Germany)
6. Leibniz Institute for Molecular Pharmacology (FMP), 13125 Berlin (Germany)

A common animal model of chemical hepatocarcinogenesis was used to examine the utility of transcriptomic and proteomic data to identify early biomarkers related to chemically induced carcinogenesis. N-nitrosomorpholine, a frequently used genotoxic model carcinogen, was applied via drinking water at 120 mg/L to male Wistar rats for 7 weeks followed by an exposure-free period of 43 weeks. Seven specimens of each treatment group (untreated control and 120 mg/L N-nitrosomorpholine in drinking water) were sacrificed at nine time points during and after N-nitrosomorpholine treatment. Individual samples from the liver were prepared for histological and toxicogenomic analyses. For histological detection of preneoplastic and neoplastic tissue areas, sections were stained using antibodies against the placental form of glutathione-S-transferase (GST-P). Gene and protein expression profiles of liver tissue homogenates were analyzed using RG-U34A Affymetrix rat gene chips and two-dimensional gel electrophoresis-based proteomics, respectively. In order to compare results obtained by histopathology, transcriptomics and proteomics, GST-P-stained liver sections were evaluated morphometrically, which revealed a parallel time course of the area fraction of preneoplastic lesions and gene plus protein expression patterns. On the transcriptional level, an increase of hepatic GST-P expression was detectable as early as 3 weeks after study onset. Comparing deregulated genes and proteins, eight species were identified which showed a corresponding expression profile on both expression levels. Functional analysis suggests that these genes and corresponding proteins may be useful as biomarkers of early hepatocarcinogenesis.

• OSTI ID: 21344805
• Journal Information: Toxicology and Applied Pharmacology, Vol. 241, Issue 2; Other Information: DOI: 10.1016/j.taap.2009.08.020; PII: S0041-008X(09)00364-0; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTIBODIES
BIOLOGICAL MARKERS
CARCINOGENESIS
CARCINOGENS
DRINKING WATER
ELECTROPHORESIS
FUNCTIONAL ANALYSIS
GENES
GLUTATHIONE
LIVER
MORPHOLINES
NITROSO COMPOUNDS
RATS
TOXICITY
AMINES
ANIMALS
BODY
DIGESTIVE SYSTEM
DRUGS
ETHERS
GLANDS
HETEROCYCLIC COMPOUNDS
HYDROGEN COMPOUNDS
MAMMALS
MATHEMATICS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
OXYGEN COMPOUNDS
PATHOGENESIS
PEPTIDES
POLYPEPTIDES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RESPONSE MODIFYING FACTORS
RODENTS
VERTEBRATES
WATER